Cellular interactions which occur during an immune response are regulated by members of several families of cell surface receptors, including the tumor necrosis factor receptor (TNFR) family. The TNFR family consists of a number of integral membrane glycoprotein receptors many of which, in conjunction with their respective ligands, regulate interactions between different hematopoietic cell lineages (Smith et al., The TNF Receptor Superfamily of Cellular and Viral Proteins: Activation Costimulation and Death, 76:959-62, 1994; Cosman, Stem Cells 12:440-55, 1994). Three receptor members of this family are (1) BCMA, B Cell Maturation Antigen (Gras et al., Int. Immunol. 17:1093-106, 1995 and Hatzoglou et al., J. Immunol., 165: 1322-30, 2000); (2) TACI, transmembrane activator and CAML-interactor (von Bülow and Bram, Science 228:138-41, 1997 and WIPO Publication WO 98/39361)) and (3) BAFF-R, also known as BLyS/BLyS receptor 3 (BR3), (Thompson et al., Science, 293: 2108-11, 2001). These receptors are known to bind one or both TNF ligands-B Lymphocyte stimulator (BLyS also known as BLyS, TALL-1, ztnf4 and THANK) (see, e.g., Shu et al., J. Leukoc. Biol. 65: 680-683 (1999)) and a proliferation-inducing ligand (APRIL) (see, e.g., Hahne et al., J. Exp. Med. 188: 1185-1190 (1998)). Specifically, TACI and BCMA are known to bind both BLyS and APRIL and BAFF-R binds only BLyS.
A number of APRIL and/or BLyS antagonists have been developed in order to block the binding of the ligands to the receptor members of the family, in order to block results of this binding which include but should not be limited to B cell co-stimulation, plasmablast and plasma cell survival, Ig class switching, enhanced B-cell antigen presenting cell function, survival of malignant B cells, development of B-1 cell function, B cell development beyond the T-1 stage, and complete germinal centre formation. Some of these molecules can also bind to and block the effect of APRIL on B cells and other components of the immune system (Dillon et al. (2006) Nat. Rev. Drug Dis. 5, 235-246). Molecules that have been developed to affect B cell function by interfering with BLyS and/or APRIL binding include BLyS antibodies such as Lymphostat-B (Belimumab) (Baker et al, (2003) Arthritis Rheum, 48, 3253-3265 and WO 02/02641); receptor-extracellular domain/Fc domain fusions proteins such as TACI-Ig, including one particular embodiment, atacicept (U.S. Patent Application No. 20060034852), BAFF-R-Fc (WO 05/0000351), and BCMA-Ig or other fusion proteins utilizing receptor extracellular domains. A further class of APRIL and/or BLyS antagonists include other molecules relying on BLyS binding ability to block binding to its receptors such as AMG 623, receptor antibodies, and other molecules disclosed in WO 03/035846 and WO 02/16312.
Not as well characterized as BLyS, APRIL's role as a ligand in this receptor family in the disease process is still being investigated (for a general review, see, Dillon et al. (2006) Nat. Rev. Drug Dis. 5, 235-246). However, this ligand, sometimes alone and sometimes in combination with BLyS, has been found to be elevated in a number of autoimmune related diseases: bullous pemphigoid (Watanabe et al., J. Dermatol Sci. 46: 53-60, 2007 (APRIL only)); systemic sclerosis (Matsushita et al., J. Rheumatol. 34: 2056-62) (APRIL and BLyS)); atopic dermatitis (Matsushita et al., Exp. Dermatol. 17: 197-202, 2008 (APRIL only)), and rheumatoid arthritis patients who have been treated with various drugs (Tan et al., Arthr. Rheum. 48:982-992, 2003 (APRIL and BLyS, see Table 1 for treatments)).
There remains a need in the art for further identification of expression patterns of these TNFR ligands that are statistically associated with autoimmune disease, such as rheumatoid arthritis (RA) and its severity. Information as to the timing of such ligand levels, for example, increased levels present at early and/or pretreatment stages of the disease is a particular need outstanding in the art. Such information is important for identifying individuals who have a propensity toward developing such autoimmune diseases, are in an active disease state, predicting the future severity of disease and for identifying those that will respond favorably to APRIL and/or BLyS antagonist treatment of these diseases. The present invention addresses this need by providing an APRIL expression pattern associated with autoimmune diseases, particularly early or pretreatment rheumatoid arthritis and providing diagnostic tests determining the presence of this expression pattern, namely increased APRIL expression in serum for those suffering from early stage RA as compared to levels seen in healthy controls.